9
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found

      Exogenous BH4/Bcl-2 Peptide Reverts Coronary Endothelial Cell Apoptosis Induced by Oxidative Stress

      research-article

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background: Vascular endothelium undergoes apoptosis when exposed to reactive oxygen species (ROS), including hydrogen peroxide and superoxide radicals. ROS are believed to be the cause of damage to small vessels during ischemia-reperfusion injury and of arterial damage during atherosclerosis. Hydrogen peroxide-induced apoptosis is mediated through the inhibition of Bcl-xl activity and caspase-3 and caspase-9 activation. The BH4 domain of the Bcl-2 family members is responsible for their antiapoptotic activity. The BH4 domains of Bcl-2 and Bcl-xl inhibit cytochrome c release and the loss of mitochondrial membrane potential. Methods and Results: The purpose of this project was to study the antiapoptotic effect of cell-permeant derivative of Bcl-2 (BH4 peptide) on endothelial cells exposed to stress conditions. BH4 peptide was conjugated to the cell-permeable peptide TAT and was applied to endothelial cells under conditions of serum starvation and hydrogen peroxide treatment. TAT-BH4 reduced caspase-3 activity and prevented apoptotic cell death. Conclusion: Our results indicate that TAT-BH4 peptide can protect endothelial cells from ROS-induced apoptosis.

          Related collections

          Most cited references8

          • Record: found
          • Abstract: found
          • Article: not found

          Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome.

          Apoptosis is an evolutionarily conserved cell suicide process executed by cysteine proteases (caspases) and regulated by the opposing factions of the Bcl-2 protein family. Mammalian caspase-9 and its activator Apaf-1 were thought to be essential, because mice lacking either of them display neuronal hyperplasia and their lymphocytes and fibroblasts seem resistant to certain apoptotic stimuli. Because Apaf-1 requires cytochrome c to activate caspase-9, and Bcl-2 prevents mitochondrial cytochrome c release, Bcl-2 is widely believed to inhibit apoptosis by safeguarding mitochondrial membrane integrity. Our results suggest a different, broader role, because Bcl-2 overexpression increased lymphocyte numbers in mice and inhibited many apoptotic stimuli, but the absence of Apaf-1 or caspase-9 did not. Caspase activity was still discernible in cells lacking Apaf-1 or caspase-9, and a potent caspase antagonist both inhibited apoptosis and retarded cytochrome c release. We conclude that Bcl-2 regulates a caspase activation programme independently of the cytochrome c/Apaf-1/caspase-9 'apoptosome', which seems to amplify rather than initiate the caspase cascade.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Bcl-x(L) prevents the initial decrease in mitochondrial membrane potential and subsequent reactive oxygen species production during tumor necrosis factor alpha-induced apoptosis.

            The Bcl-2 family of proteins are involved in regulating the redox state of cells. However, the mode of action of Bcl-2 proteins remains unclear. This work analyzed the effects of Bcl-x(L) on the cellular redox state after treatment with tumor necrosis factor alpha (TNF-alpha) or exogenous oxidants. We show that in cells that undergo TNF-alpha-induced apoptosis, TNF-alpha induces a partial decrease in mitochondrial membrane potential (DeltaPsi(m)) followed by high levels of reactive oxygen species (ROS). ROS scavengers delay the progression of mitochondrial depolarization and apoptotic cell death. This indicates that ROS are important mediators of mitochondrial depolarization. However, ROS scavengers fail to prevent the initial TNF-alpha-induced decrease in DeltaPsi(m). In contrast, expression of Bcl-x(L) prevents both the initial decrease in DeltaPsi(m) following TNF-alpha treatment and the subsequent induction of ROS. Bcl-x(L) itself does not act as a ROS scavenger. In addition, Bcl-x(L) does not block the initial decrease in DeltaPsi(m) following treatment with the oxidant hydrogen peroxide. However, unlike control-transfected cells, Bcl-x(L)-expressing cells can recover their mitochondrial membrane potential following the initial drop in DeltaPsi(m) induced by hydrogen peroxide. These data suggest that Bcl-x(L) plays a regulatory role in controlling the membrane potential of and ROS production by mitochondria rather than acting as a direct antioxidant.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Prevention of hypoxia-induced cell death by Bcl-2 and Bcl-xL.

              The proto-oncogene bcl-2, isolated from the t(14;18) chromosomal breakpoint in follicular B-lymphoma, and a bcl-2-related gene bcl-x (ref. 4) prevent apoptotic cell death induced by various treatments. Although a mechanism has been proposed that involves Bcl-2 activity on reactive oxygen species (ROS), expression of Bcl-2 or Bcl-xL prevents cell death induced by withdrawal of oxygen (hypoxia), which drastically decreases the net formation of oxygen free radicals and does not increase oxidized lipid, protein or DNA. Furthermore, neither ROS scavenger nor inhibitor of ROS scavenger affects cell death, regardless of the expression of Bcl-2 or Bcl-xL. Thus our data suggest that Bcl-2 and Bcl-xL exert an anti-cell death function by a mechanism other than regulation of ROS activity.
                Bookmark

                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2004
                April 2004
                21 April 2004
                : 41
                : 2
                : 202-207
                Affiliations
                aPharmacology Section, Department of Molecular Biology, University of Siena, Siena, and bLifetech s.r.l., Florence, Italy; cDepartment of Pharmacology and Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Tex., USA
                Article
                77408 J Vasc Res 2004;41:202–207
                10.1159/000077408
                15031604
                99e820da-4c5a-4423-88f7-eac31bd71d00
                © 2004 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 12 August 2003
                : 20 December 2003
                Page count
                Figures: 2, Tables: 1, References: 15, Pages: 6
                Categories
                Research Paper

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Endothelium,BH4/BcL-2,Apoptosis,Oxidative stress

                Comments

                Comment on this article